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An ISPE guidance document, four years in the making, brings risk-based thinking, statistics, and Lean Six Sigma to cleaning validation.
leaning is such a basic concept that it may be difficult to view scientifically, but getting it right, and validating the approach taken, is critical to patient safety and drug quality. Some pharmaceutical manufacturers may still approach cleaning validation in a somewhat random way, using imprecise and outdated methods.
Andrew Walsh, principal and owner of the PharmaClean Group, LLC and an industry professor in Stevens Institute of Technology’s Pharmaceutical Manufacturing and Engineering program, has been an outspoken advocate of changing the status quo. He urges pharmaceutical industry professionals to apply risk-based principles and science, and concepts such as Lean Six Sigma and Process Analytical Technology (PAT) to their cleaning validation programs.
Walsh led the global multidisciplinary team that drafted the science, risk and statistics-based Cleaning Process Development and Validation for ISPE (1).
Pharmaceutical Technology spoke with Walsh about the guidance, which is expected to be published in 2015.
Cleaning validation limitsPharmTech: What’s wrong with the idea of limits, as they’re currently defined and used by pharmaceutical manufacturers?
Walsh: First, companies are applying them inconsistently. Back in 1992, the Pharmaceutical Manufacturers Association (now PhRMA) surveyed industry professionals and found that they were using 44 different criteria, based either on dose (e.g., 1/10th of a therapeutic dose or 1/1000th of the lowest dose, or 1/50th of the maximum therapeutic dose), or on default limits (e.g., no greater than 1 ppm or 3 ppm) (2).
Fourteen years later, the Parenteral Drug Association (PDA) surveyed its members and found the same disparity in practice, with respondents using dose-based only, or a combination of dose-based and default. Most used 1/1000th as the dose limit and a majority used 10 ppm as the default limit.
But the limits themselves are inconsistent. In some cases (for some compounds and at some facilities), these limits will leave large amounts of API residue, and in others, small amounts nearly impossible to measure. The 10 ppm default was added to account for this problem, but this value is arbitrary and some companies even have trouble meeting it.
PharmTech: Do dose-based and default cleaning validation limits differentiate between compounds, based on potential risk to the patient or operator?
Walsh: The current method of limit setting is not science-based. Some manufacturers will take the lowest dose of any given API or drug, divide by a thousand, and set limits based on the results, even though they may not really be safe.
Most of the time, however, the limits are set too low, so that cleaning validation runs fail when there really is no need and the residue levels present absolutely no risk to the patient.
But setting cleaning validation limits is a big deal. The industry has set them incorrectly for years, using reverse logic. That’s why the ISPE publication is so important, especially the sections dealing with statistical analysis. Also important are the concept of measuring the level of risk through process capability.
Today, many manufacturers use an acceptable daily exposure limit of 1/1000th but that fails to take into account potential product risk. As a result, a 1/1000th limit set for low-dose aspirin is much lower than the limits that have been set for some drugs with potentially teratogenic or immunogenic effects.
The pharmaceutical industry is unique in that it has an enormous amount of data on its compounds available from toxicological and clinical studies and these can be used to set appropriate limits for patient exposure. So it’s important to have a toxicologist and pharma manufacturing professionals work together on setting limits based on real risks and plant floor realities, and not just by simply taking a dose and dividing it by a number.
Concepts from ICH Q9 and ISPE’s RiskMaPP guide will also be very important in setting science-based limits for API and detergent residue.
Working with toxicologistsPharmTech: Should toxicologists be working more closely with manufacturing and quality teams at pharma companies?
Walsh: At some companies, they already are, but other manufacturers are not using their expertise enough. I would like to see a closer connection between Toxicology departments and QA and validation.
Pharmaceutical toxicologists are mainly PhDs, and tend to be a tightly knit group. Many have known each other for decades. They actually all meet once a year, and have done a lot of work on how to set limits, but they tend to publish in their own specialized journals, which does not get the message out to the rest of the industry.
Generally, toxicologists are getting more closely involved in GMP issues today, but more of them need to be given the GMP perspective, and some better understanding of how the GMP world works, from people in that world. A cross-functional perspective will be very important in many situations, for example, in setting limits for early discovery compounds.
Scientific approach to cleaning validationPharmTech: Are more companies embracing the more scientific approach to cleaning validation?
Walsh: I see it starting to happen. I also see a move to risk-based tools using statistics, and drawing from the FDA’s revised process validation guidance. But I also feel that many workers don’t have a strong mastery of statistics or a clear understanding of risk and how to measure it, and are reluctant to revise their standard operating procedures (SOPs).
Lean manufacturingPharmTech: What role do you see Lean Six Sigma playing in cleaning validation and cleaning?
Walsh: Lean Six Sigma concepts are very applicable to cleaning validation; so applicable that the original name for my company was ‘Clean6Sigma’ and we even trademarked and use the term.
The key goals for Lean Six Sigma are eliminating waste and reducing variability, and that can apply to cleaning validation and cleaning, too. More manufacturers need to ask themselves such questions as ‘Why are we rinsing for 15 minutes?’
I have made Value Stream Maps of cleaning processes, and there is clearly a lot of wasted time and water in most cleaning processes. For example, why should a procedure take an hour when it could easily be done in two minutes? Many companies are discovering that capacity issues are closely tied to cleaning, so there is a real need to shorten cycle times, but it can be challenging, since it requires revalidation.
Process analytical technologyPharmTech: What role could process analytical technology (PAT) play in cleaning validation, and cleaning in general?
Walsh: PAT has a lot of potential. We have been doing some work with GE Analytical Instruments (Sievers) in the area of total organic carbon (TOC) measurement, using their portable system. This way, instead of taking swab samples to the lab, you take the lab to the line. With their instrument, there is a real promise of parametric release of equipment after cleaning, and this is one of the goals of the ISPE guide.
PharmTech: What other analytical techniques should be used to improve cleaning validation?
Walsh: High-pressure liquid chromatography is commonly used and also a good tool, but so is simple visual inspection in low- to moderate-risk situations. We are working with companies right now on a simple, cost effective program using standard coupons for qualifying operators to release equipment visually. TOC, conductivity, and visual inspection used together in a comprehensive program could save pharmaceutical manufacturers a lot of time.
There is a definite need to move away from the old ‘three batches’ and dose-based approach, towards continuous monitoring where necessary. TOC, conductivity, and visual inspection will help lead the way.
In addition, manufacturers should pay close attention to equipment design and invest in equipment that can be thoroughly and easily cleaned. They should also be subjecting their current and new SOPs to risk assessments, to eliminate any problems before they can occur.
1. A.Walsh, Pharm. Engineer, 31 (6) (November/December, 2011).
2. A. Walsh, Pharm. Engineer. 31 (4), (July/August, 2011).
Article DetailsPharmaceutical Technology
Vol. 39, No. 7
Pages: 44-45, 50
When referring to this article, please cite it as A. Shanley, "Getting Scientific About Cleaning Validation," Pharmaceutical Technology 39 (7) 2015.